SREBP-1a activation by HBx and the effect on hepatitis B virus enhancer II/core promoter

Hepatitis B virus (HBV) X protein (HBx) plays an important role in HBV pathogenesis by regulating gene expression. Sterol regulatory element binding protein-la (SREBP-1a) is a key transcriptional factor for modulating fatty acid and cholesterol synthesis. Here we demonstrated that HBx increased mature SREBP-la protein level in the nucleus and its activity as a transcription factor. We further showed that the up-regulation of SREBP-la by HBx occurred at the transcriptional level after ectopic expression and in the context of HBV replication. Deletional analysis using SREBP-la promoter revealed that the sequence from 436 to 398 in the promoter was required for its activation by HBx. This promoter region possesses the binding sequences for two basic leucine zipper (b-ZIP) transcription factors, namely C/EBP and E4BP4. Mutagenesis of the binding sequences on the SREBP-1a promoter and ectopic expression experiments demonstrated that C/EBP alpha enhanced SREBP-la activation by HBx, while E4BP4 had an inhibitory effect. C/EBPa was able to significantly reverse the inhibitory activity of E4BP4 on SREBP-1 a promoter. These results demonstrated that HBx activates SREBP-la activity at the transcription level through a complex mechanism involving two bZIP transcription factors C/EBP and E4BP4 with C/EBP being the dominant positive factor. Finally, we showed that knocking down SREBP-1 abolishes HBV enhancer II/core promoter activation by HBx. (C) 2013 Elsevier Inc. All rights reserved.